Caveolin-1 expression is associated with a basal-like phenotype in sporadic and hereditary breast cancer

Abstract

The role of caveolin 1 (CAV1), a structural component of caveolae in breast cancer is controversial, although most studies suggest that it functions as a tumor-suppressor gene. In addition, some studies have identified CAV1 as a marker of myoepithelial cells. Since myoepithelial markers are frequently expressed in breast carcinomas with a basal-like phenotype, which are frequently occurring tumors in women with BRCA1 germline mutations, we evaluated whether CAV1 was associated with a basal-like phenotype in 509 sporadic and 47 hereditary BRCA1-/BRCA2-associated carcinomas. Immunohistochemistry was performed on tissue microarrays and cases were classified as having a basal-like-phenotype if they were estrogen-receptor- and HER2-negative but cytokeratin 5/6- and/or epidermal growth factor receptor-positive. In sporadic carcinomas, CAV1 expression was found in 21 out of 496 valuable cases (4.2%). A basal-like-phenotype was found in 53 out of 498 (10.6%) cases. A strong association was found between CAV1 expression and a basal-like-phenotype, since 52% of tumors that expressed CAV1 had this phenotype, compared with only 9% of CAV1-negative carcinomas (p<0.001). CAV1 was expressed in six (12.8%) familial cases, five of which had a basal-like-phenotype (p = 0.009). Moreover, these six CAV1-positive cases were BRCA1 tumors. The difference in the frequency of CAV1 expression between BRCA1- and BRCA2-associated tumors was statistically significant (p = 0.024). In conclusion, this study reports for the first time CAV1 expression in BRCA1 and BRCA2 hereditary breast cancer and identifies CAV1 as a marker associated with a basal-like-phenotype in both hereditary and sporadic breast cancer.

Growth of hormone-dependent MCF-7 breast cancer cells is promoted by constitutive caveolin-1 whose expression is lost in an EGF-R-mediated manner during development of tamoxifen resistance

“…To this end, Joshi et al [60] have recently shown phosphorylated caveolin-1 to co-operate with Rho/ROCK and FAK-dependent signalling pathways promoting tumour cell invasion and metastasis in breast cancer. Such studies are consistent with clinical data showing a positive correlation between caveolin-1 expression (although distinction between phosphorylated and nonphosphorylated forms not addressed) and poor patient survival in highly aggressive invasive breast cancers [42][43][44]61]. The induction of caveolin-1 and the presence of a pool of phosphorylated caveolin-1 in gefitinib treated TAM-R cells may have profound implications for the overall function of caveolin-1 in these cells and for the clinical management of tamoxifen-resistant breast cancers involving the use of EGF-R inhibitors [62].…”

“…These include amongst others the activation of the EGFR/RAS/ERK signalling pathway, increased cell proliferation and cell migration, initiation of mammary gland dysplasia, enhanced anchorage independent growth and metastatic potential. Conversely, several clinico-pathological studies correlate caveolin-1 over-expression with aggressive features of certain breast cancers, most notably the basal-like and inflammatory invasive subtypes [42][43][44]. However, none of these studies have explored the functional role of caveolin-1 in the development of hormone resistant breast cancer.…”

Dasatinib, an orally active small molecule inhibitor of both the src and abl kinases, selectively inhibits growth of basal-type/“triple-negative” breast cancer cell lines growing in vitro

“…While other genes may be derived from the analysis of large microarray datasets, the biologic relevance of these genes makes them plausible predictive markers for defining a population of breast cancers that may respond to a src-targeted therapeutic like dasatinib. In addition, both moesin and caveolin-1 have been identified as markers for basal breast cancers [30,31].…”

Basal-like and triple-negative breast cancers: a critical review with an emphasis on the implications for pathologists and oncologists

“…5 More recently, a subgroup of lobular carcinomas has been shown to express high-molecular-weight cytokeratins, 41 however it remains to be determined whether these cases truly show a basal-like transcriptome. The majority of basal-like breast cancers lack or show low levels of ER and PR, lack HER2 protein overexpression and HER2 gene amplification, whereas they express genes and proteins usually found in 'basal'/myoepithelial cells of the normal breast including high-molecular-weight cytokeratins (5/6, 14 and 17), 17,19,21,42 P-cadherin, 43 caveolins 1 and 2, 44,45 nestin, 46 aB crystallin, 47,48 CD109, 49,50 and EGFR 17 and, in a minority of cases, harbor EGFR gene amplification 51 or aneusomy. 52 p53 immunohistochemical expression or TP53 gene mutations is observed in up to 85% of cases, 53,54 and alterations of the pRB and p16 G1/S cell-cycle checkpoint are remarkably prevalent in these cancers.…”